Immunogenetic data in MS implicate that specific genes within the MHC protect against the development of MS. of the oligodendrocytethat is definitely, the myelin sheaths. PATHOLOGY Multiple sclerosis (MS) Rasagiline 13C3 mesylate racemic affects scattered areas of the central nervous system having a predilection for periventricular white matter, brainstem, spinal cord, and optic nerves.1 The plaques are characterized by main demyelination (destruction of myelin sheaths with preservation of axons) and death of oligodendrocytes (myelin-producing cells) within the center of the lesion. During the early development of the plaque, perivascular inflammatory cells (lymphocytes, plasma cells, macrophages) invade the compound of the white matter and are thought to play a critical part in myelin damage.2 This process is followed by extensive gliosis by astrocytes and aberrant attempts at remyelination with oligodendrocytes proliferating in the edges of the plaque.1 In addition, immunoglobulins are deposited within each plaque.3 Whether the principal effector cells that mediate demyelination are T cells or macrophages is unfamiliar. Efforts to type the cells that infiltrate the brain in MS have yielded conflicting results.4, 5, 6, 7 Both CD8+ (cytotoxic/suppressor) T lymphocytes and CD4+ (helper/inducer) T lymphocytes surround the MS plaque. The relative proportions of T-cell subsets are controversial. Some investigators possess found an excess of CD8+ cells in the perivascular cuffs at the edge of the lesion.7 Others have found an excess of CD4+ cells.4 These discrepancies probably result from examination of the plaques at different phases of their evolution. Recent experiments have analyzed antigens of the major histocompatibility complex (MHC) in the brains of individuals with MS.8 The MHC is a set of closely linked genes that play a central role in the control of immune reactions to self and foreign antigens. This function is definitely of particular importance because CD4+ and CD8+ T cells identify foreign antigen in the context of class II (HLA-DR, la) or class I (HLA-ABC) MHC gene products, respectively. The class II gene products, found primarily on macrophages and B cells, are important in demonstration of antigen to T cells. Class I gene products are on the majority of cells in the body and are important in the generation of the cytotoxic response against viruses. The central nervous system is unique because MHC antigens normally are not present on neurons and glial cells.8 In MS, however, Rasagiline 13C3 mesylate racemic class I and class II MHC-positive astrocytes are found with high frequency in active lesions. The class I-reactive glia are primarily associated with T-cell infiltrates, whereas class II-reactive astrocytes are found in many lesions, individually of the composition of inflammatory cells. Thus, class I and II MHC-positive astrocytes might play a role in local antigen demonstration to T cells. In addition, the simultaneous presence of high numbers of class I MHC-positive astrocytes and CD8+ cells in acute lesions suggests the possibility that CD8+ cells play a role as cytotoxic T cells during early development of the lesion. The final consequencethat is definitely, demyelinationin chronic active plaques may be attributable to several immunologic mechanisms, including receptor-mediated endocytosis by macrophages, cytotoxicity by T cells, or lymphokine launch. IMMUNOGENETICS AND IMMUNOLOGY One piece of evidence that provides an important idea to the pathogenesis of MS is the association between susceptibility and specific MHC haplotypes.9 Northern Caucasians with MS have an overrepresentation of the A3, PKCA B7, DR2, and Dw2 histocompatibility alleles with relative risks of 2 to 3 3 for the class I MHC alleles (A3, B7) and 4 to 5 for class II MHC alleles (DR2, Dw2). Because linkage disequilibria exist between these class I alleles and DR2, the possible improved representation of one group of alleles may merely reflect this trend. The indefinite association between susceptibility and MHC haplotypes suggests that either more than one gene is definitely involved or a strong environmental agent breaks through to disease in the absence of the MS susceptibility allele. The rate of recurrence of event of A2, B12, DR7, and Dw7 is definitely decreased in Rasagiline 13C3 mesylate racemic individuals with MS.9 The data that pertain to this occurrence are in much Rasagiline 13C3 mesylate racemic better agreement, suggesting that some MHC alleles may protect against MS. Investigators have also reported that some MHC alleles (DR2) are associated with more Rasagiline 13C3 mesylate racemic progressive disease whereas others (DR3) are associated with more benign disease.10 Studies in various populations (American blacks, Japanese, Arabs, Israeli Jews) have also shown an association with MHC but with different alleles in each case. The risk of MS developing among first-degree relatives of individuals with MS is definitely improved 15- to 20-fold over the risk in the general population.9 This finding may reflect either genetic factors or shared environmental agents. Attempts to analyze linkage between disease and HLA haplotypes in siblings affected by MS have substantiated a loose link between MS and MHC but do not permit conclusions.